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Continued from Previous……

It would have become clear by now that the most important link in the chain of gene therapy is the ‘Vector’. Vectors transport the genes or gene-modified cells to the target site in human body. We shall conclude this topic with a discussion on Vectors and the challenges faced by the gene therapy. In the earlier part, I had mentioned that viruses are the most favored vectors. McKinsey published a report recently about the ‘promise of viral vectors’, and I shall partake some portion from there. I shall try to stay away from heavy technicalities and keep it simple to understand.

Gene insertion, replacement, modification may take place inside the body, in which the gene is inserted into a viral vector for transporting to the target cell. Or the gene manipulation may take place outside the body, in which case, certain cells are taken out, modification is done in the lab, and the modified cells are placed back in the body. In both cases, viral vectors are used.

Viral vectors are in multiple uses. A recent example of using viral vectors is the use of adenovirus-vector in COVID vaccines successfully.

Viral vector-based gene therapies use modified viruses as drug-delivery vehicles to introduce specific DNA sequences. The main reason for using viruses is their ability to get into human cells, which is different from bacteria who reside outside the cells and cause infection. It should be inferred from here that a massive viral infection would cause massive damage to cells, and thus may be deadlier than bacterial infection.

Presently, most gene therapies use one of the three virus types: adeno-associated-virus (AAV) vectors, adenovirus vectors and lentivirus vectors.  AAV and Adenovirus vectors are typically used in gene therapies when these are given for cell modification inside the body. Lentivirus vectors are used where the cells are modified outside the body.

State of Progress

There is a lot of excitement around gene therapy presently. Earlier, it was considered that the high cost of gene therapies would make these impossible to commercialize. ZOLGENSMA for SMA by Novartis was priced at 2.12 million US$ for one-dose-therapy and got a lot of flak. However, strategic payment plans have made it a highly successful launch. More than 600 infants with SMA were administered ZOLGENSMA during the first ten months of its launch. This success has opened the doors for more high-priced products.

Gene modification techniques have already been refined through extensive research since the human genome project.

New Challenges to Gene Therapy

“The current generation of viral-vector gene therapies represents the culmination of decades of biological and clinical research. As more patients have received these therapies, it has become clear that three fundamental challenges will restrict the applicability of viral vectors.

Ongoing work to address these challenges is generating technological innovations that have the potential to leapfrog current therapies and unlock the potential of viral vectors”.

  1. As mentioned earlier, our immune system recognizes viral vectors as foreign bodies and thus produces antibodies against it, thereby rendering them useless. It may even happen to the gene therapy itself. Most Bone Marrow transplants thus may be rejected within a few hours of insertion.
  2. Immunity against viral vectors may affect the efficacy of gene therapy. Many patients, probably up to 60%, may have pre-existing. Immunity against the viral vector used in therapy. CanSinoBio, for example, reported reduced efficacy of its COVID-19 vaccine in individuals who had already developed antibodies against adenovirus-5 which it had used for drug delivery.
  3. Viral vectors may trigger unintended response in the form of infection and illness. On the contrary, it may increase the efficacy through eliciting higher response. Some researchers suggest that the short durability is due to this factor. The overall concern about immune response to viral vectors is well-placed.
  4. Currently, large number of viral particles are given to the patient because of uncertainly in reaching the specific target. The large doses present two problems. One, it is very expensive to manufacture large doses. Two, the incidence of adverse reactions increases. It is therefore necessary to work towards reducing the dose.

There are few more challenges, but these are technically complex and may be omitted from our discussion.

Sum Up

Gene therapy may rightly be termed as the future of healthcare. It will deliver targeted therapies for treatment of rare, genetic, congenital, or even common diseases. The questions of morality, efficacy and safety are still being grappled with.


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